CVPR 03-26-14 10-11am Coupling & Calcium I - Beam Flashcards
Elicitation of contraction of cardiac muscle
As in skeletal muscle, contraction is elicited by an increase in the myoplasmic [Ca2+]…. binding of Ca2+ to troponin on thin filaments enables the force-producing interaction between thin filaments & the myosin heads of the thick filaments.
Intracellular store of Ca2+ in both cardiac & skeletal muscle
Sarcoplasmic reticulum (SR) serves as the chief source of the Ca2+ that causes contraction; Release of Ca2+ originates at junctions between terminal cisternae of SR (junctional SR, jSR) and plasma membrane, or plasma membrane invaginations termed transverse tubules (t-tubules).
Ca2+ channels at junction btwn jSR and plasma membrane
On the plasma membrane side of the junctions is a type of voltage-gated Ca2+ channel [dihydropyridine receptor (DHPR)]; On junctional SR, different category of Ca2+ channel termed ryanodine receptor (RyR).
Necessity of Ca2+ in Cardiac vs. Skeletal Muscle
Cardiac Muscle: Excitation-Contraction coupling DOES REQUIRE entry of external Ca2+; …….Skeletal Muscle: ECC does NOT require entry of external Ca2+…… in both forms of striated muscle (cardiac & skeletal), Ca2+ binds to troponin on thin filaments and activates contraction
Ca2+ Channels in Cardiac vs. Skeletal Muscle:
Cardiac: CaV1.2 + other subunits …….Skeletal: CaV1.1 + other subunits
Ryanodine Receptors in Cardiac vs. Skeletal Muscle
Cardiac: RyR2 isoform…….Skeletal: RyR1 isoform
Sequence of events during excitation and contraction of cardiac muscle cells:
- Ca2+ enters via DHPR (“L-type Ca2+ channel”) —> 2. Ca2+ activates RyR2 —> 3. Causes much larger flux of Ca2+ from SR into myoplasm —> 4. Ca2+ activates contraction by binding to troponin on thin filaments
Events during Relaxation of cardiac muscle cells is:
Ca2+ is removed from the myoplasm by: (i) SERCA2 pump located in longitudinal SR ….. (ii) NCX Na+/Ca2+ exchanger in junctional domains of plasma membrane and t-tubules……(iii) PMCA pump in surface membrane (1 Ca2+ per cycle)…….SERCA2 dominates since SR surrounds each myofibril; requires less energy since VSR»0. NCX is next in importance and can be arrhythmogenic.
Relaxation mechanisms (removers of Ca2+): in order of importance
SERCA>NCX»PMCA
How Ca2+ current from of L-type channels is balanced (removed)
Balanced (Ca2+ removed) via surface extrusion mechanisms
Action of SERCA2 pump in removing Ca2+ from myoplasm
Action of SERCA2 pump in removing Ca2+ from myoplasm
2 Ca2+ per cycle…..Ca2+ diffuses w/in SR to terminal cisternae, where it binds to calsequestrin (low affinity, high capacity Ca2+ binder)….. In steady-state, Ca2+ released from SR is recycled back into SR by SERCA2, while surface extrusion balances L-type Ca2+ current.
Why use Ca2+ from SR instead of just extracellular Ca2+?
From SR, Ca2+ doesn’t have to go very far to act…rapid & uniform action throughout the cell. Also, energetically favorable to have this Ca2+ recycling mechanism, near to site of action. Less energy needed to release from low-afffinity calsequestrin in the SR than to move extracellular Ca2+ through the membrane.
Action of NCX to remove Ca2+ from myoplasm
NCX works against Ca2+ concentration gradients & voltage to get Ca2+ out cell…but, doesn’t use ATP to accomplish this….rather, it is driven by the downhill influx of Na2+ to accomplish the uphill efflux of Ca2+….. 3 Na+ go in for 1Ca2+ out = net charge of +1 entering cell —> provides depolarizing drive
Change in direction of NCX sodium/calcium exchanger depends on…
Direction depends on both membrane potential (Vr) & gradients for Na+ & Ca2+ (E-Na, E-Ca).
Directionality of NCX
In principle, NCX can run either direction, and it briefly runs backwards during the AP upsweep, driving a little bit of the trigger Ca2+ for contraction….. As soon as we repolarize, NCX does it main job of extruding Ca2+ As Ca2+ goes in, Na+ out, net flow of +1 in —> provides depolarizing drive
Timing of Ca2+ release from NCX
If Ca2+ is released from the SR at the wrong time (i.e., in a resting cardiomyocyte), it can cause Na+ influx via the NCX backwards…if it is a big enough influx, this cause create an AP during diastole —> delayed afterdepolarizations —> arrhythmias
Heart failure – defn. & action of cardiac glycosides
HF= insufficient CO, typically due to lack of contractile force….. Formerly, cardiac glycosides (e.g., digitalis) were a common treatment —> inhibit Na/K ATPase (extrudes Na+ from myoplasm) —> inhibition causes increased myoplasmic [Na+] —> reduced extrusion of Ca via NCX (secondary effect of increase intracellular Na+…NCX can’t exchange as much influx of Na2+ for efflux of Ca2+)
Cardiac glycosides replaced by what…
Because of many negative side effects, they are no longer the standard treatment…Instead, beta blockers, ARBs, diuretics and DHPS are used to reduce peripheral vascular resistance.
Bockage of L-type channels in cardiac vs. vascular muscle
If DHPs equally blocked L-type channels in cardiac & vascular muscle, the reduced vascular resistance would be offset by a reduced force of cardiac contraction….But, this doesn’t occur..… Must be that DHPs preferentially reduce vascular resistance over the force of contraction: (1) Vascular Ca2+ channels are more sensitive to DHPs than are those in the heart; (2) DHPs prefer interacting with active channels (vascular muscle channels, esp. during diastole, much more active than cardiac channels)…thus, don’t cause problems w/HF pts
